Field of the Invention
This invention is related to 4-benzyl piperidine alkylsulfoxide heterocycles. The compounds of this invention are selectively active as antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is also directed to the use of 4-benzyl piperidine alkyl sulfoxide heterocycles as neuroprotective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, macular and other retinal degenerative diseases, hypoglycemia, anxiety, psychosis, asthma, glaucoma, CMV retinitis, urinary incontinence, tinnitus, aminoglycoside antibiotics-induced hearing loss, convulsions, migraine headache, chronic pain, depression, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington's Disease. A particularly preferred use of the compositions of this invention is in the treatment of Parkinson's Disease.
4-Benzyl piperidine analogs that are useful as subtype-selective NMDA receptor antagonists are described in PCT International Publication No. WO 97/23216. However, piperidine analogs having sulfoxide functionality are not described.
Benzylpiperidine derivatives are also disclosed in U.S. Pat. No. 5,698,553, as having the formula: ##STR1##
in which PA1 R.sup.1 is H, Hal or nitro, PA1 R.sup.2 is a benzyl group, which is unsubstituted or substituted by Hal on the aromatic portion, in the 2-, 3- or 4-position of the piperidine ring, with the proviso that R.sup.2.noteq.4-benzyl, i.e., R.sup.2 is not in the 4-position of the piperidine ring, if X is --CO--, Y and Z are --CH.sub.2 and R.sup.1 is H, PA1 R.sup.3 is H or A, PA1 X is --O--, --S--, --NH--, --CO-- or --SO.sub.2 --, PA1 Y is --CH.sub.2 --, --O--, --S--, --NH-- or alternatively --CO-- if X is --CO-- and Z is --NH-- or --NA--, PA1 Z is --CH.sub.2 --, --C(A).sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CO--, --NH--, --NA--, --O--, --S-- or a bond, wherein X-Y or Y-Z is not --O--O--, --S--S--, --NH--O--, --O--NH--, --NH--NH--, --O--S-- or --S--O--, PA1 A is alkyl having 1-6 C atoms, PA1 B is O or both H and OH, i.e, PA1 Hal is F, Cl, Br or I and PA1 n is 0, 1 or 2 and their salts.
together with the ##STR2##
carbon atom to which B
is bonded,
The compounds are said to be useful for the treatment of cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's, Parkinson's, or Huntington's disease, cerebral ischaemias or infarctions. However, subtype selectivity is not indicated and, again, piperidine analogs having sulfoxide functionality are not suggested or described.
Excitatory amino acid receptor antagonists that block NMDA receptors are recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's disease [T. Klockgether, L. Turski, Ann. Neurol. 34, 585-593 (1993)], human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease [P. T. Francis, N. R. Sims, A. W. Procter, D. M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington's disease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S. A. Lipton, P. A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994); and C. F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and references cited therein.]. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A).
Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) in Nakanishi's lab in 1991 provided an initial view of the molecular structure of the NMDA receptor [Nature 354, 31-37 (1991)]. There are several other structurally related subunits (NMDAR2A through NMDAR2D) that join NR1 in heteromeric assemblies to form the functional ion channel complex of the receptor [Annu. Rev. Neurosci. 17, 31-108 (1994)]. The molecular heterogeneity of NMDA receptors implies a future potential for agents with subtype selective pharmacology.
Many of the properties of native NMDA receptors are seen in recombinant homomeric NR1 receptors expressed in Xenopus oocytes. These properties are altered by the NR2 subunits. Recombinant NMDA receptors expressed in Xenopus oocytes have been studied by voltage-clamp recording, as has developmental and regional expression of the mRNAs encoding NMDA receptor subunits. Electrophysiological assays were utilized to characterize the actions of compounds at NMDA receptors expressed in Xenopus oocytes. The compounds were assayed at four subunit combinations of cloned rat NMDA receptors, corresponding to three putative NMDA receptor subtypes [Moriyoshi, et al. Nature 1991, 354, 31-37; Monyer et al, Science 1992, 256, 1217-1221; Kutsuwada et al, Nature 1992, 358, 36-41; Sugihara et al, Biochem. Biophys Res. Commun. 1992, 185, 826-832].
Novel 4-benzyl piperidines that have enhanced subtype selectivity would be highly desirable, particularly for the treatment of Parkinson's disease.